A negative ("nonreactive") RPR test result is compatible with a person not having syphilis. However, a person may have a negative RPR test and still have syphilis since, in the early stages of the disease, the RPR often gives negative results. This is a false negative RPR.

The RPR test is sometimes positive in the absence of syphilis. For example, a false positive RPR can be encountered in infectious mononucleosis, lupus, the antiphospholipid antibody syndrome, hepatitis A, leprosy, malaria and, occasionally, pregnancy.

The VDRL (Venereal Disease Research Laboratory) test is similar to the RPR test. It is also designed to detect an antibody substance in the bloodstream when syphilis is present but, as with the RPR, early syphilis infections may give a false negative result. The VDRL, like the RPR, can also give false positive results.